Morin induces autophagy-dependent ferroptosis in colorectal cancer cells by inhibiting the AURKB-UCHL3 interactions.

[BACKGROUND] Colorectal cancer (CRC) poses a significant threat to human health, and its underlying mechanisms require further exploration. Morin, a natural flavonoid, exhibits anti-CRC activity, but its molecular mechanisms remain unclear. This study aimed to evaluate its anti-CRC effects and elucidate its molecular mechanisms to provide new insights for CRC treatment.

[METHODS] Molecular docking predicted potential binding between morin and AURKB. Experimental validation included qPCR, Western blotting, co-immunoprecipitation, and immunofluorescence. Autophagy-dependent ferroptosis was assessed by measuring mitochondrial superoxide, MDA, GSH, and ROS levels, as well as NCOA4 and FTH1 expression.

[RESULTS] AURKB is highly expressed in CRC, and stabilized via interaction with the deubiquitinase UCHL3, which activated the PI3K/Akt/mTOR pathway and suppressed autophagy-dependent ferroptosis. This suppression was characterized by reduced mitochondrial superoxide, decreased MDA and ROS levels, elevated GSH, and upregulated FTH1. Morin disrupted the AURKB-UCHL3 interaction, promoted AURKB degradation, reversed ferroptosis inhibition, and suppressed CRC cell proliferation and migration.

[CONCLUSION] This study is the first to demonstrate that morin inhibits CRC progression by targeting the AURKB-UCHL3 axis to regulate autophagy-dependent ferroptosis, providing experimental evidence for its therapeutic potential in CRC treatment.